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Development of molecular pharmacological strategies against oxidant stress-induced steroid resistance

Research Project

Project/Area Number 12670784
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionTokyo Women's Medical University

Principal Investigator

YOSHIOKA Toshimasa  Tokyo Women's Medical University, School of Medicine, Assoc. Prof., 医学部, 助教授 (60146438)

Co-Investigator(Kenkyū-buntansha) SUGANUMA Taiyo  Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 助手 (00328379)
TSUKAHARA Fujiko  Tokyo Women's Medical University, School of Medicine, Assoc. Prof., 医学部, 助手 (40119996)
MURAKI Takamura  STIGATTokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (50051446)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsGlucocorticoid / Glucocorticoid receptor / Oxidant stress / Heat shock protein / Free radicals / Nitric oxide / Antioxidants / Estrogen / エストロゲン受容体 / 熱ショックタンパク質 / エンドトキシン / 腎不全 / 尿毒症物質 / 尿細管障害 / ステロイド受容体 / 酸化的ストレス / 血管内皮細胞 / 尿毒性物質 / インドキシル硫酸 / 慢性腎不全 / 細胞質-核間輸送 / 分子間相互作用 / HSC70
Research Abstract

1. Reduced steroid sensitivity in cells exposed to oxidant stress : Using green fluorescent protein-tagged receptor and reporter gene assays, impaired glucocorticoid-dependent nuclear import of receptor and transcriptional activation by oxidant stress was demonstrated. In a separate study, estrogen-dependent transcriptional activation by estrogen receptor-a was found to be also impaired by oxidant stress. Thus, oxidant stress impairs steroid-dependent gene transcription.
2. Role of heat shock proteins (HSPs) in steroid sensitivity : In the model of cellular oxidant stress, an introduction of a member of HSPs, HSC70, restored steroid sensitivity. In vivo model of endotoxin-induced vascular permeability change, induction of HSP70 by heat stress prevented subsequent endotoxin-induced microvascular permeability change in mouse skin. These results indicated molecular pharmacological manipulation to induce HSPs may protect cellular steroid resistance induced by oxidant stress.
3. Mechanisms of free radical production in pathophysiological conditions and applications of antioxidant drugs : As a mechanism of cellular injury in progressive renal disease, some uremic toxins, organic acids, were newly found to induce renal proximal tubular injury by oxidant stress after reabsorbed by the cells vial transporter-medicated uptake. Some antioxidant drugs were found to have nitric oxide scavenging ability. Such effect may modify the pharmacological effect of the drug in specific paphophysiological conditions where nitric oxide and oxygen-derived free radicals co-exist.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxins up-regulate plasminogen activator inhibitor-1 via NF-κB and free radical-dependent mechanism in human renal proximal tubular cells"Kidney International. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxins induce proximal tubular injury via organic anion transporter 1-medicated uptake"British Journal of Pharmacology. 135. 553-563 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suganuma T, Yoshioka T, et al.: "Effect of heart stress on lipopolysaccharide-induced vascular permeability change in mice"Journal of Pharmacology and Experimental Therapeutics. 303. 656-663 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshioka T, et al.: "Anti-NO action of carvedilol in cell-free system and in vascular endothelial cells"British Journal of Pharmacology. 129. 1530-1535 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsukahara F, Yoshioka T, et al.: "Molecular characterization of HSC54, a novel variant of human heat-shock cognate protein 70"Molecular Pharmacology. 58. 1257-1263 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 吉岡俊正, 塚原富士子: "融合遺伝子発現系によるタンパク質可視化技術の分子薬理学的応用"日本薬理学会雑誌. 116. 36-42 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxin up- regulate plasminogen activator inhibitor-1 vial NF-κB and free radical dependent mechanism in renal proximal tubular cells."Kidney International. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxins induce proximal tubular injury via organic anion transporter-1-mediated uptake"British Journal of Pharmacology. 135. 553-563 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suganuma T, Yoshioka T, et al.: "Effect of heat stress on lipopolysaccharide-induced vascular permeability change in mice."Journal of Pharmacology and Experimental Therapeutics. 303. 656-663 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshioka T, et al.: "Anti-NO action of carvedilol in cell-free system and in vascular endothelial cells."British Journal of Pharmacology. 129. 1530-1535 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsukahara F, Yoshioka T, et al.: "Molecular characterization of HSC54, a novel variant of human heat-shock cognate protein 70."Molecular Pharmacology. 58. 1257-1263 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxins up-regulate plasminogen activator inhibitor-1 via NF-κB and free radical-dependent mechanism in human proximal tubular cells"Kidney International. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Motojima M, Yoshioka T, et al.: "Uremic toxins induce prosimal tubular injury via organic anion transporter-1-medicated uptake"British Journal of Pharmacology. 135. 553-563 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suganuma T, Yoshioka, et al.: "Effect of heat stress on lipopolysaccharide-induced vascular permeability change in mice"Journal of Pharmacology and Experimental Therapeutics. 303. 656-663 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Motojima M, Yoshioka T., et. al.: "Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake"British Journal of Pharmacology. 135. 555-563 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ohba K, Yoshioka T, et al.: "Identification of two novel splicing variants of human type II iodothyronine deiodinase mRNA"Molecular and Cellular Endocrinology. 172. 169-175 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshioka,T.: "Anti-NO action of carvedilol in cell-free system and in vascular endothelial cells."British Journal of Pharmacology. 129. 1530-1535 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 吉岡俊正: "融合遺伝子発現系による蛋白質可視化技術の分子薬理学的応用"日本薬理学会雑誌. 226. 36-42 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 吉岡俊正: "一酸化窒素および構成型熱ショックタンパク質70によるグルココルチコイド作用の修飾機構の解析"臨床薬理. 31. 331-332 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsukahara,F.: "Molecular and functional characterization of HSC5, a novel variant of human heat-shock cognate protein 70."Molecular Pharmacology. 58. 1257-1283 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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